Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor
View Patent ↗A process for production of cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV is provided which employs a BOC-protected amine of the structure prepared by subjecting an acid of the structure to reduce amination by treating the acid with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified phenylalanine dehydrogenase/formate dehydrogenase enzyme concentrate (PDH/FDH) and without isolating treating the resulting amine of the structure 2 with di-tert-butyl dicarbonate to form the BOC-protected amine.
1. A method for making a compound of the structure
or a salt thereof, the method comprising:
treating (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid first with an alkyl chloroformate or mesyl chloride in the presence of a base, and then with ammonia to form (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate; and
deprotecting the (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate to form the compound or salt.
2. A method according to claim 1 , further comprising
saponifying (1S,3S,5S)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate to form the (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid.
3. A method according to claim 2 , further comprising
treating a mixture of syn and anti isomers of (3S)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate with aqueous methylamine to separate (1S,3S,5S)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate from the mixture; and
recovering the (1S,3S,5S)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate.
4. A method according to claim 3 , further comprising
treating (S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate with diethylzinc and chloroiodomethane to form the mixture of syn and anti isomers of (3S)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate.
5. A method according to claim 4 , further comprising
esterifying (S)-5-oxopyrrolidine-2-carboxylic acid to form ethyl (S)-5-oxopyrrolidine-2-carboxylate;
reacting the ethyl (S)-5-oxopyrrolidine-2-carboxylate with di-tert-butyl dicarbonate to form (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate;
treating the (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate with lithium triethylborohydride, then with base to form the (S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate.
6. A method for making a compound of the structure
or a salt thereof, the method comprising:
treating (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate with diethylzinc and chloroiodomethane to form (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate; then
deprotecting the (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate to form the compound or salt.
7. A method according to claim 6 , further comprising
saponifying (S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate to form a 3-carboxylate intermediate;
reacting the 3-carboxylate intermediate with methanesulfonyl chloride to form a mixed anhydride intermediate; and
reacting the mixed anhydride intermediate with ammonia to form the (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate.
8. A method according to claim 7 , further comprising
esterifying (S)-5-oxopyrrolidine-2-carboxylic acid to form ethyl (S)-5-oxopyrrolidine-2-carboxylate;
reacting the ethyl (S)-5-oxopyrrolidine-2-carboxylate with di-tert-butyl dicarbonate to form (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate;
treating the (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate with lithium triethylborohydride, then with base to form the (S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate.
9. A method according to claim 6 , further comprising
treating an alkali (S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylate with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride to form an activated ester; and
treating the activated ester with ammonia to form the (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate.
10. An isolated compound selected from
(S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate;
(S)-tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate;
(1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate; and
(1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid.
11. An isolated compound according to claim 10 , that is (S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate.
12. An isolated compound according to claim 10 , that is (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate.
13. An isolated compound according to claim 10 , that is (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate.
14. An isolated compound according to claim 10 , that is (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid.